1. Technical Field
The present invention relates to pharmaceuticals for use as therapeutic agents. More specifically, the present invention relates to pharmaceuticals containing therein gold for use as therapeutic agents.
2. Background of the Invention
Gold, in elemental form, has been employed for centuries as an antipruritic to relieve the itching palm. In more modern times, the observation by Robert Koch in 1890 that gold inhibited Mycobacterium tuberculosis in vitro led to trials in arthritis and lupus erythematosus, thought by some to be tuberculous manifestations. Later observations of success in treating chronic arthritis stimulated interest in gold therapy (chrysotherapy). At present, gold is employed in the treatment of rheumatoid arthritis; usually it is reserved for patients with progressive disease who do not obtain satisfactory relief from therapy with NSAIDs. However, gold compounds are among the agents that are used in an attempt to arrest the progress of the disease and to induce remissions; these are sometimes called disease-modifying drugs, although this is probably a misnomer (Edmonds et al., 1993). Since degenerative lesions do not regress once formed, there is an increasing tendency to attempt to induce remission early in the course of the disease. Such therapy is often initiated with gold, which although potentially beneficial, causes a high incidence of toxicity (Felson et al., 1992; Cash and Klippel, 1994).
Gold compounds can suppress or prevent, but not cure, experimental arthritis and synovitis due to a number of infectious and chemical agents. Gold compounds have minimal antiinflammatory effects in other circumstances and cause only a gradual reduction of the signs and symptoms of inflammation associated with rheumatoid arthritis. Although many effects of these drugs have been observed, which, if any, are related to the therapeutic effects of gold in rheumatoid arthritis is unknown. Perhaps the best hypotheses relate to the capacity of gold compounds to inhibit the maturation and function of mononuclear phagocytes and of T cells, thereby suppressing immune responsiveness. Decreased concentrations of rheumatoid factor and immunoglobulins often are observed in patients who are treated with gold.
In experimental animals, gold is sequestered in organs that are rich in mononuclear phagocytes, and it selectively accumulastes in the lysosomes of type A synovial cells and other macrophages within the inflamed synovium of patients who are treated with gold compounds. Moreover, the administration of gold thiomalate to animals depresses the migration and phagocytic activity of macrophages in inflammatory exudates, and chrysotherapy reduces the augmented phagocytic capacity of blood monocytes from patients with rheumatoid arthritis. Other mechanisms of action of gold compounds have been suggested, but none is generally accepted. These include inhibition of prostaglandin synthesis, interference with complement activation, cross-linking of collagen, and inhibition of the activity of lysosomal and other enzymes, including protein kinase C, in T cells.
Considerable research has been focused on the development of water-soluble gold-containing compounds because of their potential in medical applications [1]. The first application of gold-containing compounds came from their use in rheumatoid arthritis. The compounds used in the treatment of rheumatoid arthritis were aurothiomalate (Myocrisin) and aurothioglucose (Solgano) as depicted in FIG. 1. In 1985, another gold containing compound, auranofin, [(2,3,4,6-tetra-O-aceytl-1-thio-β-D-glucopyranosato-S)-(triethylphosphine) gold(I)] was shown to be effective for the treatment of rheumatoid arthritis [2,3]. Several studies have demonstrated that this agent is superior to the traditional chrysotherapeutic drugs. Auranofin and related gold(I) compounds have been found to be active against interperitoneal P388 leukemia and are also cytotoxic to specific tumor cells [4,5]. Mirabelli et al. screened the μ-[bis(diphenylphosphino)ethane] digold complex [dppe(AuCl)2] (FIG. 2) for antitumor activities [6]. Such digold complexes rearranged to give tetrahedral complexes of the type [Au(dppe)2].
The tetrahedral arrangement of ligands around gold (as in Au(dppe)2; FIG. 2) allowed better stabilization of the metal center through chelate effects. Such tetrahedrally-bound phosphine ligands around the gold center are more inert to substitution by potential thiolate ligands that could be encountered in a biological environment.
It was suggested that the mechanism of action for [Au(dppe)2]Cl was the formation of DNA protein cross-links [7,8]. The lack of affinity of gold(I) for oxygen and nitrogen containing ligands resulted in poor reactivity with the bases of DNA.
The gold compound [Au(dppe)2]Cl demonstrated marked activity against peritoneal cancer cells. However, this compound was found to be only slightly active against solid tumor models. This compound could not proceed to clinical trials due to problems with cardiotoxicity as revealed in preclinical toxicology studies [9].
Failure to identify an effective gold-containing antitumor agent stems from the difficulties associated with the development of gold compounds with optimum hydrophilicity/lipophilicity, toxicity and activity toward specific tumors. Therefore, an improved understanding of the molecular and biochemical mechanism of gold compounds can provide the impetus for new advances in the antitumor applications of gold compounds. It would also be useful to develop an antitumor gold compound which is not toxic to the patient.
It would therefore be useful to develop pharmaceuticals to develop stable non-radioactive gold complexes for use as chemotherapeutic agents.